The Pictet-Spengler reaction uses catalytic acid to convert a β-arylethylamine and an aldehyde or ketone to a substituted tetrahydroisoquinoline. First β-arylethylamine attacks the carbonyl carbon, forming a tetrahedral intermediate, which is dehydrated to afford the corresponding Schiff base. Upon protonation, a 6-endo-trig cyclization occurs, disrupting ring aromaticity. Loss of an aryl proton then restores aromaticity, giving rise to the tetrahydroisoquinoline product.
- Reagents: Catalytic Protic Acid (HCl, H2SO4, etc.) or Lewis Acid (BF3·OEt2)
- Reactant: β-Arylethylamine, Aldehyde or Ketone
- Product: Substituted Tetrahydroisoquinoline
- Type of Reaction: Condensation
- Bond Formation: N-C and C-C
Lab Tips
- Only β-arylethylamines with electron-donating substituents afford high yields.
- This reaction is influenced by the number of electron-donating groups on the ring. For instance, two alkoxy groups allows the reaction to proceed under physiological conditions, important in the biosynthesis of alkaloids.
- Carrying out the reaction with a slight excess of the carbonyl compound ensures the complete consumption of the amine in either protic or aprotic solvents.
- The Schiff base can be prepared separately and later subjected to a protic or Lewis acid.
Mechanism
Top Citations
Original Paper
Related Reactions
- Synthesis of Cyclopentenones
Related Compounds
- Catalytic Acid
- Aldehyde
- Ketone
